5, 10-methylene-19-nor cortical hormones



United States Patent 3,253,095 5,10-METHYLENE-19-NGR CORTiCAL HORMONES Lawrence H. Knox, Mexico City, Mexico, assignor to Syntex- Corporation, Panama, Panama, a corporation of Panama No Drawing. Filed Mar. 19, 1964, Ser. No. 353,243 19 Claims. (Cl. 260-397.45)

The present invention relates to certain novel cyclopentanOphenanthIene derivatives and to the method for making the same.

More particularly this invention relates to certain novel 5,10-methylene-l9-nor cortical hormones substituted at 0-3 by lower alkyl radicals or at C-1 and C-3 by lower alkyl, alkenyl or alkinyl radicals. These compounds are represented by the following formulas:

In the above formulas, R and R represent lower alkyl, alkenyl or alkinyl radicals which may be the same or different; R represents hydrogen or an acyl radical of less than 12 carbon atoms; R represents hydrogen, amethyl or ,H-methyl; R represents a lower alkyl group, R represents hydrogen or a lower alkyl group and Y represents hydrogen, keto or B-hydroxy.

The acyl groups above referred to are derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, or aromatic, and may be substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate, and ,B-chloropropionate.

The compounds of the present invention are valuable cortical hormones with high anti-inflammatory, low catabolic, glycogenic and thymolytic activities. In addition they have anti-androgenic, antigonadotrophic and anti-estrogenic properties.

3,253,065 Patented May 24, 1966 'ice The method for producing these compounds is illustrated by the following sequence of reactions:

In the above formulas R, R R R and R have the same meaning as heretofore set forth.

In practicing the process illustrated above a lot-alkyl, alkenyl or alkinyl-17,20;20,21-bismethylenedioxy-5,10- methylene-l9-nor-pregnan compound (I) obtained by selective Oppenauer oxidation at C-3 of a 17,20;20,21- bismethylenedioXy-A -pregnene-3B,l9-diol to the corresponding A -3-keto compound, reaction of this compound with 2-chloro-l,1,2-trifluorotriethylamine to produce a mixture of the 17,20,20,2l-bismethylenedioxy-S,10-methylene-l9- nor A pregnen 3 one and the 17,20;20,21-bismethylenedioxy 5,10 seco 5,19 cyclo 105 fluoro-A pregnen-3-one, as describedin my copending application Serial No. 286,931, filed June 11, 1963, now U.S. Pat. No. 3,184,484, and final treatment of the 17,20;20,2lbismethylenedioxy 5,10 methylene 19 nor A -pregnen-S-one with a Gn'gnard reagent to produce a mixture of the lot-substituted l7,-20;20,2l-bismethylenedioxy-id0- methylene 19 nor pregnan 3 one and 3 substituted 5,10 seco 5,19 cyclo A pregnatriene compounds, which are separated by chromatography, as described in my copending patent application Serial No. 346,074, filed Feb. 20, 1964, is treated with a lower alkyl, alkenyl or alkinyl magnesium halide such as methyl magnesium bromide, ethyl magnesium bromide, vinyl magnesium bromide, ethinyl magnesium bromide, propargyl magnesium bromide, etc., in an inert organic solvent such as ether, benzene, tetrahydrofuran, and the like, at a temperature comprised between room temperature and reflux, for a period of time of between 1 to 6 hours, to produce the corresponding 3-alkyl, alkenyl or alkinyl-S-hydroxy- 17,20;20,21 bismethylenedioxy 5,10 methylene 19- nor-pregnane compounds (H). The latter compounds (II) are then dehydrated, preferably with 2-chloro-l,1,2- trifluorotriethylamine, in an inert organic solvent such as tetrahydrofuran, methylene chloride, acetonitrile, etc., at room temperature for a prolonged period of time, preferably overnight, or by using other conventional methods such as treatment with thionyl chloride in pyridine or anhydrous hydrogen chloride in acetic acid solution, to produce a mixture of the corresponding 1,3-disubstituted- A -pregnenes (III) and 1,3-disubstituted A -pregnenes (IV) which are separated by chromatography on Florisil or neutral alumina. 7

Catalytic hydrogenation of III and IV in the presence of a heavy metal-catalyst, preferably in the-presence of a palladium-charcoal catalyst and using a lower aliphatic alcohol as solvent, produces the saturated compounds, by absorption of 1 molar equivalent of hydrogen when R and R are lower alkyl groups or from 2 to 5 molar equivalents when R and/0r R are alkenyl or alkinyl radicals. There are thus obtained the 1a,3-dialkyl-l7, 20;20,21 bismethylenedioxy 5,10 methylene 19- nor-pregnanes (V) (mixture of 3a and 3B-isomers, the latter predominating), which can be purified by fractional crystallization or chromatography. This hydrogenation is preferably conducted at room temperature and atmospheric pressure, however, these conditions are not critical.

Upon hydrolysis of the 17,20;20,2l-bismethylenedioxy group in compounds III, IV and V under conventional conditions, preferably by heating with a 60% formic acid solution, the dihydroxy acetone side chain is regenerated, thus producing the 1ot,3-disubstituted derivatives of 5,lO-methylene-19-nor-A -pregnene-17a,2l-diol- 20 one, 5,10 -methylene 19 nor A pregnene 170:, 21-diol-20-one and 5,10-methylene-l9-nor-pregnane l7a, 2l-diol-20-one, as well as the 16-methyl derivatives thereof (VI, VII and VIII; R =H).

The formation of the ll-oxygenated compounds are produced by microbiological oxidation as, for example,

by incubation with a culture of Curvularia lunata and is illustrated by the following reactions:

I onion o=o =0 NW RS X MR! 3 B R4 n I VIII XI In the above formulas R, R R R and R have the same meaning as described heretofore and X represents fi-hydroxy or keto.

In practicing the above reactions, compounds VI, VII and VIII are microbiologically oxidized, as by incubation with Curvularia lunata, to produce the corresponding llp-hydroxy compounds, i.e., the la,3-disubstituted derivatives of 5,lit-methylene-l9-nor-A -pregnene-115,1701, 21-triol-20-one (IX: R =H; X=fi-OH); the 1a,3-disubstituted derivatives of 5,lO-methylene-l9-nor-A -preg nene-l1fi,17a,21-triol-20-one (X: R =H; X=fi-OH); the 1a,3-disubstituted derivatives of 5,10-methylene-l9- nor-A -pregnene-1 1B,17a,21 triol 20 one (X: R =H; X= 3-OH) and the 1a,3-disubstituted derivatives of 5,10- methylene 19-nor-pregnane-llfi,l7a,2l-triol-20-one (XI: R =H; X= 3-OH) as well as the l6-methyl derivatives thereof.

The above mentioned compounds having the dihydroxy acetone side chain (VI, VII, VIII, IX, X and XI; R =H) are converted into the corresponding 2l-monoesters by treatment with acid anhydrides or acid chlorides of less than 12 carbon atoms in pyridine solution, in a conventional manner.

Upon oxidation of the 21-monoesters of the llfl-hydroxylated compounds (IX, X and XI; R =acyl, X=fi-OH) with chromium trioxide in acetone solution or chromium trioxide in aqueous acetic acid, there are produced the respective ll-keto derivatives (IX, X and XI; R =acyl; X=keto), which can be saponified with a dilute solution of potassium hydroxide at low temperature and optionally reesterified by conventional methods.

In another aspect of the present invention illustrated by the reaction scheme below, catalytic hydrogenation of the 3-alkyl, alkenyl or alkinyl derivatives of 17,20; 20-2l-bismetl1ylenedioxy 5,10 seco-S,19-cyclo-A pregnatriene (XII) (obtained as described in the aforementioned copending application Serial No. 346,074, filed Feb. 20, 1964), using eventually the same conditions as hereinbefore described for the 1,3-disubstituted conipounds, give rise to the 3zxand 3,8-alkyl-5,l0-methylene- 19-nor-pregnanes (XIII), (the BB-isomer predominating) by absorption of 2 to 4 molar equivalents of hydrogen, depending on the substituent at G3. The protecting group of the side chain is then hydrolyzed by treatment with 60% formic acid and the 3fi-alkyl-5,l0-methylene- 19-nor-pregnane-17u,21-diol 20 one compounds (XIV: R :H) are incubated with a culture of Curvularz'a lanata to produce the corresponding lid-hydroxylated compounds (XV; R =H). Conventional ester-ification of the above mentioned compounds give rise to the corresponding 21-monoesters (XIV and XVI; R acyl).

Upon oxidation of the 21-monoesters of the llfi-hydroxylated compounds with chromium trioxide, there are produced the corresponding ll-keto compounds (XVI; R =acyl) which can be' saponified and optionally reesterified, as previously described for the 1,3-disubstituted 5,IO-methylene-l9-nor-pregnenes.

The foregoing method is illustrated by the following equations:

IS U E/ U XH R CHI OR CHzO R y R 1 I R4 XVI In the above formulas R, R R and R have the same meaning as described heretofore.

The following examples serve to illustrate but are not intended to limit the scope of the present invention:

XIII

(IJEUOR C=O Example I A solution of 2.5 g. of 1a-methyl-l7,2O;20,21- bismethylenedioxy-S,l0-methylene-19-nor-pregnan-3-one in 95 cc. of ether was added dropwise, over a 15 minute period,

to 25 cc. of 4 N-methyl-magnesium bromide solution in 6 Example 11 A solution of l g. of the foregoing compound in 7 cc. of dry pyridine was cooled to l0 C., treated with 0.4 cc. of thionyl chloride and the mixture allowed to stand for 10 minutes at this temperature. Ice-water was added and the product extracted with methylene chloride. The organic extract was washed with water, hydrochloric acid solution, sodium bicarbonate solution and water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed on 50g. of neutral alumina, thus producing 1a,3-dimethyl 17;20,20,2l-bismethylenedioxy-S,l 0-methylene-19-nor-A -pregnene and 1a,3-dimethyl-17,20;20,21abisrnethylenedioxy 5,-10 methylene-19- nor-A -pregnene in pure form.

Example III To a solution of 1 g. of 10,3-dirnethyl-17,20;20,2;1-bismethylenedioxy-19-nor1pregnan-3-ol in 25 cc. of anhydrous tetrahydrofuran there was added 1.5 molar equivalents of Z-chloro-l,1,2 trifluorotriethylamine, and the reaction mixture was kept at room temperature overnight. It was then evaporated to dryness under reduced pressure and the residue chromatographed on 50 g. of Flor-isil, to produce 1a,3-dimethyl-l7,20;20,2l bismethylenedioxy-i 1O-methylened9-nor-A -pregnene and 1u,3-dimethyl-17, 20;20,2l-bismethylenedioxy 5,"10 methylene-19-nor-A pregnene, identical to that obtained by the method of Example H.

Example IV By following the method of Example I, 1a,16a-dimethyl-17,20;20,2'l bismethylenedioxy-S ,10 methylene-19-norpregnan-3-one, lot-vinyl =17,'20;20,21abismethylenedioxy- 5,10-metl1ylene19-nor-pregnan-3-one and 1u-ethinyl-17, 20;20,2'l-bismethylenedioxy-5,10-methylene 19-nor-pregnan-3-one were converted respectively into 1a,3,16oc-flmethyl-17,20;20,2l-ibismethylenedioxy 5,10 methylenel9-nor-pregnan-3-ol, 1aavinyl-3-methyll7,20;20,21-bismethylenedioxy-S,l 0-methylenel9-nor-pregnan-3-ol and 1a-ethinyl-3-methyl-17,20;20,21 bismethylenedioxy-5,10- methylene-19-nor-pregnan-3-ol.

Upon treatment of these compounds with thionyl chloride in pyridine, in accordance with the method of Example II, there were obtained respectively: 1a,3,l6utrimethyl-17,20;20,21 bismethylenedioxy 5,10-methy1- ene- 19-nor-A -pregnene and 10;,3,16a-trimethyl-17,20;20, 2l1-4bismethylenedioxy -5,lO-methylene l9-nor-A3 pregnene; la-vinyl-3 methyl-17,20;20,2l-bismethylenedioxy- 5,10-methylene-19-nor-A -pregnene and 1a-vinyl-3-methyl-17 ,20;20,21-bisrnethylenedioxy 5,10-methylene-19-no-r- A -pregnene and 1a-ethinyl-B-methyl-17,20;20,21 bismethylenedioxy-S,10-methylene-19-nor-A pregnene and 1m ethinyl-3-methyl-l7,20;20,21 bismethylenedioxy 5,10- methylene-19nor-A -pregnene.

Example V Into a suspension of 1 g. of lu, 3,16a-trimethyl-l7,20; 20,21 -bisrnethylenedioxy-5 ,1 0 methylene-l9-nor-pregnan- 3-01 in 35 g. of glacial acetic acid, there was passed a slow stream of dry hydrochloric acid; after 10 minutes all the solid material was dissolved. The gas was passed through the reaction mixture for a total of 5 hours. The solution was concentrated to about one third its initial volume by distillation under reduced pressure at 35 C., then it was poured into ice-water. The product was extracted with ether, Washed to neutral, dried and evaporated to dryness. Chromatography of the residue on 50 g. of Florisil afforded 10:,3,16m-trimethyl-17,20;Z0, 21-bismethylenedioxy-5,lO-methylene-19-nor A pregnene and 10:,3,16a-trimethyl-17,20;20,2l-bismethylenedioxy-S,1O-methylened9-nor-A -pre gnene, identical to that obtained in the preceding example.

7 Example V l A solution of g. of 1a-rnethyl-l7,20;20,21-bismethylenedioxy-S,10=rnethylene-l9-nor-pregnan-3-one in 250 cc.

8 1a-vinyl-3-ethyl-165-methyl-17,20;20,2l-bismethylenedioxy-S,IO-methylene-19-nor-A -pregnene and 1a-vinyl-3-ethy1-16/8-methyl-17,20;20,21-bismethylenedioxy-S, 1O-methylene-19-nor-A pregnene;

of thiophene-free benzene was treated with 27.5 cc. of 4 5 1 hi 1-3. 1-16 h 1.17,2Q;2(),21.bi h 1 N methylmagnesuim bromide in ether and the mixture e diox j 1Q. gh 1 -19 2 and refluxed with the exclusion of moisture for 3 hours. The l .ethinyl 3 rg yl-lfi qnethyl-17,20;2[) 21..bisme;thy1

cooled mixture was cautiously treated with excess aqueous enedimqhj 1() th 1 1 9 a ammonium chloride solution and the product isolated by ethyl acetate extraction. The extract was washed with 10 E l VIII water, dried over anhydrous sodium sulfate and evaporated to dryness. A solution of 1 g. of 1a,3-dimethyl-17,20;20,21 bis- Recrystallization :from methylene chloride hexane afmethylenedioxy-S,1O-methylene-19-nor-A -pregnene in 100 forded 1a53-di-II1Cthyl-17,20;2O,2I-iblSHIEthYICDBdiOXY-5,1O- cc. of methanol was hydrogenated in the presence of methylene-19-nor-pregnan-3-ol identical to that obtained 100 mg. of 5% palladium charcoal catalyst (previously in Example I. reduced) until the absorption of hydrogen ceased (1 By the same method, the compounds listed below molar equivalent). The catalyst was fil-tered OE and under I were treated with the indicated Grignard rethe filtrate evaporated to dryness. Crystallization of agent, to produce the compounds mentioned under H. the residue from acetone-ether gave the pure 10,3fl-dl- I Reagent II 1a-methyl-17,20;20,21-bismethylenedioxy-5,Ill-methylenel9-nor-preguan-3-one. 1a-viny1 17,20;20,2l-bismethylenedioxy-5,IO-methylene-IQ- nor-pregnan-B-one. 1a-ethinyl-l7,20,20,21-bismethylenedioxy-5,10-methylene- 19-nor-pregnan-3-one. 1a-n1ethyl-17,20;2O,21-bismethylenedioxy-5,IO-methylene- 19-n or-pregnan-Ii-one. 1a,16a-dimethy1-17,20;20,21-bismethylenedioxy-5,10-

methylene-l9-nor-pregnan-3-one. methyl-17,20;20,21-bismethylenedioxy-5,10-methylenel9-nor-pregnan-3-one. 1a,16B-dimethyl-l7,20;20,21-bismethylenedioxy-5,10-

methylene-lSJ-nor-pregnan-3-one. 1a-vinyl-lfifl-methyl-l7,20;20,2l-bismethylenedioxy-5,l0-

methyle ne-lQ-nor-pregnan-li-one. la-ethinyl-1Ga-methyl-l7,20;20,21-bisrnethylened1oxy-5,10-

methylene-IQ-nor-pregnan-B-one.

nude

mide.

Ethylmagnesium bromide- Vinyl-magnesium bromide.

Propyl magnesium bromide.

Propargyl magnesium bromide.

Ethinyl-magnesium bro- Methyl -magnesium bromi e. Propyl-magneslum bromide.

Ethyl-magnesium bromide Propyl magnesium bro- Example VII The compounds obtained in the preceding example were dehydrated with 2-chloro-1,l,2-trifluorotriethylamine and then ohromatographed on Florisil, in accordance with the method of Example III, to produce respectively:

1a-methyl-3-ethyl-l7,2'0;20,2l-bismethylenedioxy-S,10-

methylene-l 9-nor-A -pregnene and 1a-methyl-3 -ethyl-l 7,20;20,2 l bismethylenedioxy-S, 10-

methylene-19-nor-A -pregnene;

1a,3-d ivinyl-17,20;20,21 bismethylenedioxy-S,IO-meth- Iyene-IQ-nQr-A -pregnene and 1a,3-divinyl-17,20;20,2 1-bismethylenedioxy-5, 1 O-methylene-19-nor-A -pregnene;

1a-ethinyl-3-propy1-17,20;20,2l-bismethylenedioxy-S, 10-

methylene-19-nor-A -pregnene and 1a-ethinyl-3 -propyl- 17,20;20,2 1'bisme thylenedioxy-S,

l O-methylene-19 -nor-A -pregnene la-methyl-3-propinyl-17;2 0;20,2l-bismethylenedioxy-S,

1 0-methylene-19-nor-A -pregnene and 1a-met-hyl-3 -propinyll7,20;20,2 l-bismethylenedioxy-S,

1 O-methylene-19-nor-A -pregnene;

1a, 16a-dimethyl-3-ethinyl-17,20;20,21-bismethylenedioxy-S,10-rnethylene-19-nor-A -pregnene and 1a,16a-dimethy1-3-ethinyl-17,20;20,2l-bismethylenedioxy-5,1O-methylene-19-nor-A -pregnene;

1 a-et-hyl-3-methyl-17,20;20,2Lbismethylenedioxy-S,10-

methylene-19-nor-A -pregnene and 1a-ethyl-3-metl1yl-17,20;20,2l-bismethylenedioxy-S,10-

me thylene- 1 9-nor-A -pregnene 1a,16/3-dimethy1-3 -propy1-17,20;20,21-bismethylenedioxy-S,1O-methylene-19-nor-A -pregnene and 1a,16B-dimethyl-3-propyl-17,20;20,2l-bismethylenedioxy-S l O-methylene-19-nor-A -pregnene;

me-thyl-17,20;20,21 bismethylenedioxy 5,l0-methylene- 19-nor-pregnane.

The same product was obtained when 1a,3-dimethyl- 17,20;20,2l-bismethylenedioxy-S,10 methylene 19-nor- A -prcgnene was used as starting material.

By the same method 104,3 ,16a-trimethyl-17,20;20,2l-bismethylenedioxy-S,10-

methylene-19-nor-A -pregnene,

1a-methyl-3-ethyl-17,20;20,21-bismethylenedioxy-5,10-

methylene-19-n0r-A -pregnene and 1a-ethyl-3-methyl-17,20;20,21-bismethylenedioxy-5,10-

methylene-19-nor-A -pregnene' were converted respectively into 101,313, 1 6a-trimethyl-17,20;20,21-bismethylenedioxy-5,10-

methylene-IQ-nor-pregnane,

1a-methyl-35-ethyl-17,20;20,2l-bisrnethylenedioxy-S,10-

methylenel 9-nor-pregnane and 1a-ethyl-3B-methyl-17,20;20,2l-bismethylenedioxy-S,10-

methylene-19-nor-pregnane.

Example IX 9 m were converted into the corresponding saturated deriva- 1a-ethyl-3-methyl-5,1O-methylene-l9-nor-A -pregnenetives listed under II: 17,2l-di0l-20-011e,

I II

1a,3-dlvinyl-17,20;20,21-bismethylene- 1a,3B-dimethy1-17,20;20,21-bismethylenedioxy-5,10-methylene-19-nor-A -preg'nane. diary-5,10-methylene-lQ-nor-pregnane. IaethinyI-B-propyl-U,20;?0,ZI-bismethylla-ethyl-ZiB-propyl-17,20;20,21-bismethyleneenedioxy-5,10-methylene-lQ-nor-N-pregdioxy-5,10-methylene-19-nor-pregnane. nene. 1a-methyLZi-propinyl-liflO;20,21-bisrnethyl- 1a-methy1-3 S-prpyl-17,2D;20,21-bismethy1- enedloxy-S, l0-methylene-19-nor-A enedi0xy-5,10-methylene-19-nor-pregpregneue. nane. 1a,1Gui-dimethyl-3-ethinyl-17,20;20,2l- 1a,l6a-din1ethyl-3fl-ethyl-l7,20;20,21-bisbismethylenedioxy-5,lO-methylene-19- methylenedioxy-5,IU-methylene-lQ-nornor-A -pregnene. pregnane. lwethlnyl-ikpropyl-l6a-methyl-17,20;20, la-ethyl-3fl-propyl-16a-rnethyl-17,20;20,21- 21-bismethylenedioxy-5,10-methyleneblsruethylenedioxy-5,10 rnetl1ylene-19- lg-nor-A -pregnene. nor-pregnane.

Example X 1a,165-d1methyl-3-propyl-5J0-methylene-19-nor-A pregnene-17a,21-diol-20-one,

1a,l 6fi-dimethyI-3-propyl-5,10-methylene-19-nor-A pregnene-17a,2 l-diol-ZO-one,

1 a-ViflYl-3 -ethyl-1GB-methyl-S,1O-methylene-19-nor-A pregnene- 1 7a,2 l-diol-ZU-one,

1 a-vinyl-3 -ethyl-l GB-methyl-S, l 0-rnethylene-19-nor-A pregnene-17a,21-diol-20-one,

1u-ethinyl-3 -propyl-1 6a-methyl-5,10-methylene-19-nor- In the method of the preceding example there was used 1oz 1-vinyl-3-methyl-17,20;20,2l-bismethylenedioxy- 20 5,10 methylene 19-nor-A -pregnene as starting material, and the uptake of hydrogen was of 2 molar equivalents, thus producing 1a-ethyl-3B-methyl-17,20;20,21-bismethylenedioxy-5,10-methylene-19-nor-pregnane, identical to the obtained in Examples VIII and 1X.

Example XI A -pregnene-17a,21-diol-20-one, 1a-ethinyl-3-propyl-l6a-methyl-5,l0-methylene-l9-nor- A mlxture of 1 g. of 1u,3-d1methyl-l7,20;20,21-h1s- A3 17 21 di 1 20 e methylenedioxy 9 m y "P and 1a,3,8-dimethyl-5,lO-methylene-l9-nor-pregnane-170:,21- 20 cc. of 60% formic acid was heated on the steam bath 1 for hour, cooled, diluted with water and the formed 1, 3 B 16 t i th 1 5 1() thy1 -19- r r an precipitate collected by filtranon, washed with water, dried 17 1 2 and recrystallized from acetone-hexane, thus2 producing 1 -methyI-Iifl-ethyI-S,lO-methylene-19-110r-pregnane- 1a,3 dimethyl 5,10 methylene 19 nor-A -pregnene- 21 0 1u-BthyI-BB-methYl-SJO-methylene-19-nor-pregnane- By the same method, starting from the corresponding n p pm 17,20;2 O,21-bisrnethylenedioxy derivatives obtained in the 1053 fi diethy1 5 10-methy1ene-19 nr pregnane-17 21 preceding examples there were produced: 5 1-243- 1a,3-dimethyl-5,10-methylene-19-nor-A -pregnene-1704,21- 40 1wethY1-3fi-pr0Py1-5,1o-methylene-l9-nvr-pregnanedial-20 l7a,2l-diol-20-one, 1a,3 ,1 6a-trimethyl-5 ,1 O-methylene- 19-nor-A -pregnene- 1 3 P 1 3 lo'methylene' 1 9 17 21 1 2 l7a,21 -d10l-20-0I1e, 1a,3 1 6a-trimethyl-5,l O-methylene-l 9-nor-A -pregnenefi ,1 o'methylenfi'w 17a,21 dio1 20 one, pregnane-17a,21-d1ol-2O-one and 1 a viny1 3 methy1 5,10 methy1ene 19 nor A2 pregnene 1 a-ethyl-3B-propyl-1ou-methyI-S,10-methylene-19-nor- 17a,21 diO1 20 One, pregnane-17a,21-d1o1-20-one. 1a-vinyl-3-methyl-5,1O-methylene-19-nor-A -pre nene- 17a,2l-diol-20-one, a f 18 la-ethinyl-3-methyl-5,lO-methylene-l9-nor-A -preg A strain of Curvularza lunata ATCC 13935 was grown 17 21 1 20 in a Sabounn-i-glucose-agar medium (Difco). The 1a-ethinyl-3-methyl-5,IO-methylene-19-nor-A -pregnenegrowth obtainfifi after incubating for a Week at 1 20 was suspended 1n 5 cc. of sterile water. This suspension 1a-methyl-3-ethyl-5,1O-methylene-l9-nor-A -pregn was divided in 5 portions of 1 cc. each which were em- 7 1 20 ployed for inoculating 5 Erlenmeyer flasks of 250 cc. 1 th 1 3 th 1 5 0 th 1 19 A3 n capacity containing each 50 cc. of a culture medium of 1 1 2 the following composition: 101,3-divinyl-5,lO-methylene-l9-nor-A -pregnene-l7a,21- Gl g 20 9- NLL HPO 5 1a3-d1vxnyl-5,lO-methylene-l9-nor-A -pregnene-17a,2l- 0 or diol 2tl-one, NQNQ3 g 3 1a-ethmyl-S-propyl-5,1O-methylene-19-nor-A -pregnene- K2HPO4 g 1 17a,2l-diol-20-one, Mgso fllfl o g 2 1a-ethinyl-3-propyl-5,1O-rnethylene-19-nor-A pregnene- 01 g 05 21150 Traces 1a-methyl-3 -propinyl-5, l O-methylene-19-nor-A -pregnene- F8504 71-1 0 Traces lull-(1101499116, Distilled water to complete 1 1t. 1 a-methyl-3 -prop1nyl-5 ,1O-methylene-l9-nor-A -pregnene- 17u,21-diol-20 one, The cultures were incubated under rotatory stirring 111,16a-dimethyl-3ethinyl6,10-methylene-19-nor-A for 72 hours at 25 C. The growth was homogenized pregnene-17a,21-di0l-20-one, for 1 minute in a Waring Blendor; 2 cc. portions of the 1a,l6a-dimethyl-3-ethinyl-S,l0-methylene-19-nor-A suspension thus obtained were employed for inoculating pregnene-l7a,2l-diol-ZO-one, approximately Erlenmeyer flasks containing the same 1a-ethyl-3-methyl-5,IO-methylene-19-I1or-A -pregnenemedium described above. The mixtures were incubated :,21-dl01-20-O116, 75 for 24 hours under rotatory stirring at 25 C. and 280 rpm; to each flask there was added 0.5 cc. of a solution of 0.5 g. of 111,3 dimethyl 5,10 methylene 19 nor- A -pregnene-17a,21-diol 2O-one in 50 cc. of 95% ethanol and the incubation was continued under the same conditions for 48 hours. The contents of the flasks were combined and extracted with four portions of methylene chloride. The combined extract was dried over anhydrous sodium sulfate and concentrated at low temperature to a volume of 25 cc. This solution was adsorbed on 12 g. of silica gel and eluted with methylene chloride-acetone (9:1) to produce la,3-dimethyl- ,10- methylene 19 nor A pregnene 11fl,174x,21 triol- 20-one.

By the same method the compounds mentioned below under I were converted into the corresponding llfl-hydroxylated derivatives (II):

monoacetate of 10a ethyl 3 methyl 5,10 methylene- 19-nor-A -pregnene-17a,2l-diol-l1,2O-dione and the 21- monoacetate of loz,3fi dimethyl 5,10 methylene 19- nor-pregnane-l7 0c,2 l-diol-l 1,20-dione.

Example XV I II 1a,3,16a-trimethyI-SJO-methylene-IQ- nor-N-pregnene-Ha,21-diol-20-one. 1a-ethinyl-3-metl1yl-5,IO-methylene-IQ- nor-A -pregnene-17a,21-diol-20-one. 1a,3-divinyl-5,10-methylene-19'nor- A -pregnene-17a,21-diol-20-one. 1a,3,16a-trimethy1-5,IO-methylene-lQ-nor- A pregnene-Uafl1-dio1-20-one. 1a,16a-dirnethy1-3-ethinyl-5,IO-methylene- 19-nor-A -pregnene-17a,21-diol-20-one. 1a-ethyl-3-methyl-5,10-methylene-19- nor-A -pregnene'17u,21-diol-20-one. 1a,3fi-dimethyl-5,IO-methylene-lQ-norpregnane-17a,21-diol-20-one. 111,35,16a-trimethyl-5,ldmethylene-lQ-norpregnane-17a,21-di0l-20-one. 1a-methyl-3flpropy1-5,10-methylene-19-norpregnane-17a,2Ldiol-20-one.

Example XIII Example XI A solution of 500 mg. of the 2l-monoacetate of 111,3- dimethyl 5,10 methylene l9 nor A pregnene- 1l;3,17a,21-triol-20-one in 10 cc. of acetone was cooled to 0 C. and treated under an atmosphere of nitrogen and with stirring, with a solution of 8 N chromic acid (prepared by mixing 26 g. of chromium trioxide with 23 cc. of concentrated sulfuric acid and diluting with water to 100 cc.), until the color of the reagent persisted in the mixture. It was stirred for 10 minutes further at 0-5 C. and diluted with water. The precipitate was collected, washed with water and dried under vacuum, thus afiording a crude product which upon recrystallization from acetone-hexane gave the 2l-monoacetate of 10:3 dimethyl 5,10 methylene l9 nor A pregnene-l7oz,2l-diol-11,20-dione.

By the same method, the 21-monoacetate of lu-ethinyl- 3 methyl 5,10 methylene 19 nor A pregnene- 11,8, 17oz,21 triol 2O one, the 21 monoacetate of lu,3 divinyl 5,10 methylene 19 nor A pregnenel1p3,17oz,21 triol 20 one, the 21-monoacetate of laethyl 3 methyl 5,10 methylene 19 nor A pregnene-l lfi,l7a,2l-triol-20-one and the 21-monoacetate of 111,3 3 dimethyl 5,10 methylene 19 nor pregnane- 1l/3,l7a,21-triol-20-one were converted respectively into the 21-monoace tate of la-ethinyl-S-methyl-S,lO-methylene-l9-nor-A -pregnene-l7a,21-diol-l1,20-dione, the 21- monoacetate of 101,3 divinyl 5,10 methylene 19- nor A pregnene 170:,21 diol 11,20 dione, the 21- The residue was crystallized from acetone-ether, to produce 3/3 methyl 17,20;20,2l bismethylenedioxy 5,10- methylene-l9-nor-pregnane.

Upon hydrolysis of the foregoing compound with 60% formic acid, in accordance with the method of Example XI there was obtained Bfi-methyl-S,10-methylene-19-norpregnane-170:2l-diol-20-one.

In a similar manner, starting from 3,16a-dimethyl- 17,20;20,2l bismethylenedioxy 5,10 seco 5,19- cyclo-A -pregnatriene there were obtained successively 30:,16u dimethyl 17,20;20,2l bismethylenedioxy 5,10 methylene l9 nor pregnane and 3 3,160:- dimethyl 5,10 methylene l9 nor pregnane 17a,2ldiol-20-one.

Example XVI The preceding example was repeated but using 3-vinyl- 17,20;20,2l bismethylenedioxy 5,10 seco 5,19- cyclo-A -pregnatriene as starting material, in this case there were consumed approximately 3 molar equivalents of hydrogen. There was produced as final product 3,6 ethyl 5,10 methylene 19 nor pregnane- 17u,2l-diol-20-one.

Example XVII .Example XV was repeated but 3-ethinyl-17,20;20,21- bismethylenedioxy 5,10 seco 5,19 cyclo A pregnatriene was used as starting material and the uptake of hydrogen was of approximately 4 molar equivalents. Upon hydrolysis of the bismethylenedioxy grouping there was obtained 3/3-ethyl-5,lO-methylene-19- nor-pregnane-17u,21-diol-20-one identical to that obtained In accordance with the method of Example XII, 3,3- methyl 5,10 methylene 19 nor pregnane 1701,21- diol 20 one, 3 3,160 dimethyl 5,10 methylene 19- nor pregnane 170;,21 diol 20 one and 3/8 ethyl- 5, lO-methylene-19-nor-pregnane-170:,2 l-diol-ZO-one were incubated with a culture of Curvularia lunata ATCC 13935, to produce respectively 3,3-methyl-5,lO-methylenein the preceding example.

Example XVIII 19 nor pregnane 11fi,17a,21 triol 20 one, 313,160:-

dimethyl 5,10 methylene 19 nor pregnane 115,- 17a,21 triol 2O one and 3d ethyl 5,10 methylene- 19-nor-pregnane-1 1B,17a,21tI'iO1-20-0n6.

These 11 B-hydroxylated compounds were esterified with acetic, caproic and cyclopentylpropionic. anhydrides, thus producing the corresponding 21-monoacetates, 21- monocaproates and 21-monocyclopentylproprionates.

145 21-dio1-11,20-dione were converted into the corresponding free compounds.

Example XXI In accordance with the method of Example XIII, the compounds mentioned below under I were esterified with the indicated acid anhydride, to produce the corresponding esters (II):

Example XIX In accordance with the method described in Example XIV the 21-monoacetate of 3/3-rnethyl-5,10-methylene- 19 nor pregnane 11B,17oz,21 triol 20 one, the 21- monocaproate of 313,161: dimethyl 5,10 methylene- 1 Anhydride 1r la,3 dimethyl-5,ldmethylene-lQ-nor-N- Caproic 21-monocaproate of la,&dlmethyl 5,10-

pregnene-H ,21-dil-20-0ne, goiethylene-l9 n0r-A -pregnene-17z,21-d1ol- -one. 1a,3,16atrimethy1-5,1(Lmethylene-19-nor-A Propionic. 21-mon0propionate of 1a,3,16a-trimethy1-5, pregnenedm,21-diol-20-one. oaingthy1ene-l9-n0r-A -pregnene-17a,21-

. io O-one. 1a,3-dimethy1-5,IO-methylene-lQ-nor-AL Undecenoic... 2l-monoundeccnoste o1 1a,3-dimethy1-5,10- pregnene-llfi,17a,21-trio1-204 ne. inetlhgyolene-19-110r-A -pregnene-11B,17a,21-

110 -one. 1a-ethinyl-3-methyl-5,10-methylene19-n0r-A Enanthic 2l-rnonoenanthate of 1a-ethlnyl-3-methylpregnene-17a,21-diol-20-one. (51.104211?thylene-lQmor-N-pregnerte-17a,21-

1o -one. 1a,3-divinyl-5,IO-methylene-lQ-nor-N- Caproic 21-monocaproate of 1a,3-divinyl-5,l0-

pregnene-17a,21-dio1-20-one. rgraethylene-lQ-nor-N-preg-nene-Ua,21-d1o1- one. 1a-ethinyl-3-propyl-16a-methyl-5,IU-meth- Cyclopentyl 21-monocyclopentylpropionate of la-ethinylylene-l9-n0r-A -pregnene-17u,21-diol-20-one. propiomc. 3-propyl-16a-methy1-5,Idmethylene-IQ- nor-A -pregriene-17a,21-d1ol 20-one. 1a,313-1fia-trimethyl-S,IO-methylene-lQ-nor- Propionic- 2l-monoprop1onate of 1a,3t9,16a-tr1methylpregnane-Ua,21dio1-2(%one. t51,1ti-gethylene-1Q-nor-preguano-17a,21-

1o -one. 1a-ethyl-S-methyl-5,1O rnethylene-19nor-A Undecenoic-.. 2l-monoundecenoate of la-ethyl-S-methylpregnene-llfldh,21-triol-20-one. 5,IO-methylene-19-n0r-A -pregnene11B,

17a,21-tr1o1-20-one. 1a-methyl-Bflpropyl-S,10 methylene-19-nor- Enanthic 21-monoenanthate of 1a-methyl-3B-pr0py1- pregnanedlfldh,21-trio1-20-one. 5,1O-rnethylene-19-nor-pregnane-116,1711,

21-tnol-20-one. 1a-ethinyl 3-methyl-5,IO-methylene-lQ-nor-N- Caproic 2l-monocaproate of 1a-ethinyl-3-methyl-5,

pregnene-17a,21-diol-11,20-dione. IO-methylene-l9-nor-A -pregnene-l7a,21-

diol-11,20 d1one. 1a,3-dirnethyl-5,10-methylene-lQ-nor-N- Cyclopentyl 21-1nouocyelopentylpropionate of 111,3- pregnene17a,21-diol-11,20-di0ne. prop o c. y t epregnene-fla,21-d1o1-11,20-d1one.

I claim:

1. A compound of the following formula:

19 nor pregnane 11 8,17a,21 triol 20 one and the 21-monocyclopentylpropionate of 3[3ethyl-5,10-methylene 19 nor pregnane 11B,17ot,21 \triol 20 one were converted respectively into the 21-monoacetate of 3B methyl 5,10 methylene 19 nor pregnanc- 17a,21 diol 11,20 dione, the 21 monocaproate of 35,160; dimethyl 5,10 methylene 19 nor pregnanc- 17a,21 diol 11,20 dione and the 21 monocyclopentylpropionate of 3,8 ethyl 5,10 methylene 19- nor-pregnane-17a,2l-diol-l1,20-dione.

Example XX A solution of 500 mg. of the 21-monoacetate of 1a, 3-dimethyl-5,10-methylene-19-nor-A pregnene 17a,21- diol-11,20-dione in 15 cc. of methanol was cooled to 0 C. and treated under nitrogen atmosphere with 1.5 cc. of a 4% aqueous solution of potassium hydroxide and the reaction mixture was stirred for 1 hour under an atmosphere of nitrogen at 0 C.; it was then neutralized with acetic acid and the methanol distilled under reduced pressure. The residue was triturated with water and the solid collected, washed with water, dried and recrystallized from ethyl acetate-methanol, thus producing 1u,3-dimethyl-5,1O-methylene-l9-nor-A -pregnene 17u,21 diol- 11,20-dione.

In a similar manner, the 21-monoacetate of la-ethinyl- 3-methyl-5,10-methylene 19 nor-A pregnene-17a,21- diol-11,20-dione, the 21-monoacetate of 1a,3-diviny1-5, 1O-methylene-19-nor-A -pregnene-17a,21 diol 11,20- dione, the 2l-monoacetate of la-ethyl-3-methyl 5,10- methylene 19 nor-A -pregnene-17a,21-diol-11,20-dione, the 21-monoacetate of 1a,3B-dimethyl 5,10 methylene- 19-nor-pregnane-17a-21 diol-11,20-dione, the 21-monoacetate of 3fi-methyl-5,10-methylene-19 nor pregnanc- 17a,21-diol 11,20 dione and the 21-monocaproate of 3;9,16u-dimethy1 5,10-methylene-19-nor-pregnane 17a,

Al or wherein R and R are selected from the group consisting of lower alkyl, lower alkenyl and lower alkinyl; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is selected from the group consisting of hydrogen, ot-methyl and ,B-methyl and Y is selected from the group consisting of hydrogen, B-hydroxy and keto.

2. 1oz,3-dimethyl-5,10-rnethylene-l9-nor-A pregnene- 17a,21-diol-20-one.

3. 1a,3,16a-trimethyl-5,10 methylene 19 nor A pregnene-17u,21-diol-20-one.

4. lot-vinyl 3 methyl 5,10 methylene 19 nor- A pregnene 17a,21-dio1 20 one.

5. lot-ethyl 3 methyl 5,10-methylene 19 nor- A -pregnene-115,17a-21-tri0l-20-0he.

6. 1a,3,16a trimethyl 5,1O-methylene-l9-nor-A -pregnene- 17a,21dlO1-11,20-dl0116.

7. A compound of the following formula:

wherein R and R are selected from the group consisting of lower alkyl, lower alkenyl and lower alkinyl; R is selected from the group consisting. of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is selected from the group consisting of hydrogen, a-methyl and B-rnethyl and Y is selected from the group consisting of hydrogen, B-hydroxy and keto.

8. 1u,3-dimethyl 5,IO-methylene-19-nor-A -pregnene- 17a,2l-diol-20-one.

9. 1a,3,16u-trimethyl 5,1O-rnethylene-19-nor-A -preg- Hel16-17oz,21-dlO1-20-OI16.

10. 111,3 dimethyl 5,10 methylene-l9-nor-A -pregnene-17a,2l-diol-l1,20-di0ne.

11. 1oc,3,16a trimethyl 5,10 methylene-19-nor-A pregnene-l1fi,17u,21-triol-20-one.

12. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is selected from the group consisting of hydrogen, a-methyl and B-methyl and Y is selected from the group consisting of hydrogen, B-hydroxy and keto; R represents a lower alkyl group and R is selected from the group consisting of hydrogen and lower alkyl.

13. 111,3 3 dimethyl 5,10 methylene-19-nor-pregnane-17a,2l-diol-20-0ne.

14. 1a,3 8,16m-trimethyl 5,10 methylene-19-nor-pregnane-l l/3,17a,2l-triol-20-one.

15. 1a,3fl dirnethyl 5,10 methy1ene-19-nor-preg- 113116-17oz,Z1-di0i11,20-di0118.

16. 3/3 methyl 5,10 methylene-19-nor-pregnane- 17a,21-diol-20-one.

17. 3B ethyl 5,10 methylene 19 nor pregnane- No references cited.

LEWIS GOTTS, Primary Examiner. 

1. A COMPOUND OF THE FOLLOWING FORMULA: 